Whereas many studies of the pathogenesis of Alzheimer's disease have focused on the neuronal losses that occur in the limbic cortex of these patients, the reorganization of the connections of the remaining neurons may play a significant role int he functional deficits of these patients. Our previous studies show that in aged rats (more than 24 months of age), neurons in the retrosplenial granular cortex alter their normal, mature structure and remodel their synaptic connections, likely in response to decreases in synaptic activity. Specifically,a the apical dendrites of layer II neurons withdraw from the outer half of layer I, where they are normally innervated by the axons of the anterior ventral thalamic nucleus. These dendrites subsequently arborize int he deeper half of this layer (an area that lacks thalamic innervation from the anterior ventral thalamic nucleus and an area in which t he apical dendrites of the layer II cells typically do not arborize). Further, in the aged rat, the apical dendrites of layer III neurons extend to the outer half of layer I (an area that they normally do not occupy) and appear to contract the terminals of thalamic axons in this region. Thus, in this area of the cortex the neurons in both layers II and III are engaged in dynamic reorganization in the aged rat. Subsequent studies have demonstrated that these changes occur in spontaneously hypertensive rats (SHR) but at a much earlier age (12 months); an age at which the rats are in relatively good health and can be run reliably in behavioral tests. The reorganization of the retrosplenial cortex ina the 12 month old SHR is correlated with a significant decrease in learning and memory. Further, recent findings demonstrate that the age- related plasticity of structure and function in the mature (12 months old) and even aged (more than 24 month old) SHR are prevented and/or significantly delayed by chronic antihypertensive therapy with an angiotensin converting enzyme inhibitor. Thus, the mature SHR offers an model that could significantly facilitate the study of the regulation of structure and function of limbic cortex neurons that are actively remodeling their structure and connections. The first specific aim will test the hypothesis that a local decrease in the release of acetylcholine into the retrosplenial cortex precedes (and contributes to) the age-related reorganization of neurons in this cortex. The second specific aim will test the hypothesis that an imbalance ina the brain renin-angiotensin system alters acetylcholine release in the retrosplenial cortex and thereby induces structural remodeling of the dendrites and connections in the mature SHR. The third specific aim will test the hypothesis that replacement of the cholinergic innervation of the retrosplenial cortex will delay/prevent the reorganization of layer I of the retrosplenial cortex in the aging shr. The fourth specific aim will test the hypothesis that the reorganization of the projection from the anterior thalamus to the limbic cortex leads to behavioral impairments int he mature SHR. Our general hypothesis is that the age-related remodeling of the retrosplenial cortex ina the mature SHR is the result of chronically decreased synaptic activation of the apical dendrites of the layer II neurons, i.e., use dependent plasticity.